Prostaglandins are found in virtually all tissues and glands and are extremely potent mediators of a diverse group of physiological processes (Funk, C. D. Science, 2001, 294, 1871-1875). Prostaglandins can participate in a wide range of body functions, such as the contraction and relaxation of smooth muscle (Andersson, K. E., Forman, A. Acta Pharmacol. Toxicol., 1978, 43 (Suppl. 2), 90-95), the dilation and constriction of blood vessels (Abramovich, D. R., Page, K. R., Parkin, A. M. L. Br. J. Pharmac., 1984, 81, 19-21), control of blood pressure (Anderson, R. J., Berl, T., McDonald, K. M., Schrier, R. W. Kidney International, 1976, 10, 205-215), and modulation of inflammation and immunity (Hata, A. N., Breyer, R. M. Pharmacol. Ther., 2004, 103(2), 147-166). In general, prostaglandins and related compounds are transported out of the cells that synthesize them and affect other target cells close to their site of formation, mainly by interacting with the target cell's prostaglandin receptors to stimulate or inhibit some target cell function. They also alter the activities of the cells in which they are synthesized. The nature of these effects may vary from one cell type to another, and from the target cell type.
Prostaglandin D2 (PGD2) and PGE2 are biosynthesized from the cyclooxygenase (COX) product of arachidonic acid and common prostanoid precursor prostaglandin H2 (PGH2) by the catalytic action of a class of prostaglandin synthases that includes the prostaglandin D synthases (PGDSs) and the PGESs, respectively. Methods and products exist for the measurement of PGD2 and PGE2 levels in samples derived from biological systems; however, their relative scarcity in urine due to rapid metabolism and degradation makes their use as biofluid markers for measurement of their biosyntheses impractical.
The relatively abundant PGD2 and PGE2 urinary metabolites tetranor-PGDM and tetranor-PGEM, respectively, are favorable quantification species for the assessment of PGD2 and PGE2 biosyntheses. All four species, PGD2, tetranor-PGDM, PGE2, and tetranor-PGE2 readily dehydrate to their cyclopentenone derivatives PGJ2, tetranor-PGJM, PGA2, and tetranor-PGAM, respectively. In addition, the major urinary metabolite of the prostaglandin PGF2α is tetranor-PGFM (Granström, E., Samuelsson, B., J. Am. Chem. Soc., 91, 1969, 3398-3400.).
One synthesis of tetranor-PGEM is disclosed (Lin, C., J. Org. Chem., 41(25), 1976, 4045-4047). The disclosed route began from lactone-aldehyde intermediate (I).
The disclosed route involves process for installing the prostaglandin metabolite lower chain (ω-chain) starting with (I), an intermediate that is not readily available. The ω-chain is further extended by addition of 1-dimethyl-tert-butylsilyloxy-4-pentynyllithium. Other than this disclosure, practical chemical syntheses of the tetranor-prostaglandin metabolites are not disclosed. Ready supplies of these important metabolites by controlled chemical processes would provide advantage over the current art of isolation through biosynthesis. Characterized standard compounds are potentially useful, for example, as assay standards or building blocks for preparing analogs for medicinal chemistry purposes. This present invention provides many practical chemical syntheses of the tetranor-prostaglandin metabolites beginning with the readily available hydroxyl-protected Corey lactone aldehyde.